Real-life experience on effectiveness and safety of dupilumab in adult patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Dupilumab, a fully human monoclonal antibody targeting the alpha subunit of IL-4 was recently approved for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients. OBJECTIVE: To assess dupilumab effectiveness and safety in adults with moderate-to-severe AD in a real-life Italian multicentre retrospective cohort. METHODS: Adult moderate-to-severe AD patients, referring to 39 Italian centers, received dupilumab in the context of a national patient access program. Disease assessment was performed at baseline, after 4 and 16 weeks of treatment using Eczema-Area-and-Severity-Index (EASI) score, itch and sleep numerical-rating-score (itch-NRS, sleep-NRS) and Dermatology-Life-Quality-Index (DLQI). RESULTS: A total of 109 (71 M/38F) patients was studied. There was a significant reduction in EASI score, itch-NRS, sleep-NRS and DLQI from baseline to week 4 and a further significant decline to week 16. EASI 50, EASI75 and EASI90 were achieved by 59.6%, 28.4% and 9.3% of patients at 4 weeks and by 87.2%, 60.6% and 32.4% of them at 16 weeks, respectively. Adverse events were experienced by 19.2% (21/109) of the patients and they were all mild in intensity, being conjunctivitis the most common side effect. CONCLUSIONS: Dupilumab significantly improved disease severity, pruritus, sleep loss and quality of life with an acceptable safety profile.

[An independent observatory in Vendée on ST-elevated acute myocardial infarction (the OVISCA Register). A Departmental evaluation of demographic trends, mortality and delays before treatment]. / Observatoire Vendéen indépendant des syndromes Coronarien aigus avec sus-décalage du segment ST (Registre OVISCA). Évaluation départementale, évolution démographique, mortalité, délais de prise en charge.

AIM: Mortality from acute myocardial infarction has been falling during the past 30 years. The aim of the study was to evaluate the temporal trends of demographics, mortality rates, and time to treatment in patients admitted for acute ST elevation myocardial infarction (STEMI) in Vendée. PATIENTS AND METHODS: From 2008 to 2016, 1994 patients hospitalised in CHD Vendée for STEMI <48hours were included. Two groups were compared, 838 patients admitted between 2008 and 2011 (group 1), and 1156 admitted between 2013 and 2016 (group 2). RESULTS: Between the 2 periods, mean age was comparable (63.8 vs. 64.4 years), the gender ratio decreased (from 3.15 to 2.79 ; P=0.25). The mean duration of hospital stay was 0.8 day shorter (P=0.008). Treatment at discharge was optimum in 97.5% patients versus 92% (P<0.001). Left ventricular ejection fraction was comparable (50.6% vs. 50.2%). There was a non-significant trend to a decrease in hospital mortality (from 6.3% to 4.4%; p=0.12), and 6-month mortality (from 6.9% to 5.9%; P=0.51). There was a reduction in the use of emergency call-outs (74.9% to 68.9%; P<0.01), but an increase in direct presentations from 44% to 48.7% (P<0.05). The time before calling was comparable (2.5hours vs. 2.3hours; P=04.7). The "door-to-balloon" time decreased (0.71 vs. 0.55hour; P<0.001). The mean time between pain and angioplasty increased (5.7 vs. 6.8hours; P<0.05). CONCLUSIONS: In vendee, from 2011 to 2016, hospital and 6-month mortality of STEMI trend to decrease non-significantly. The door to balloon time decreased, although emergency call-out rates and delays did not. Considerable efforts are still required with respect to patient information and education. Our registry offers an excellent tool to improve practices, the aim being to ensure its integration in the CRAC-France PCI registry.

Osteoporosis prevention: where are the barriers to improvement in a French general population? A qualitative study.

We conducted a qualitative study with French men and women in order to provide insight into individuals' experiences, behaviors, and perceptions about osteoporosis (OP) and OP care. The data showed that both sexes, but especially men, were unfamiliar with OP, did not always feel concerned, and mistrusted pharmacological treatments. INTRODUCTION: To engage actively in osteoporosis (OP) prevention, people need to have basic knowledge about the disease. The aim of this qualitative study was to explore knowledge and representations of OP care and prevention among both men and women. METHODS: Focus groups were conducted in the Rhône-Alpes Region, France, with women aged 50-85 years and men aged 60-85 years, with or without a history of fragility fracture and/or an OP diagnosis (respectively referred to as "aware" or "unaware"). A total of 45 women (23 "aware" and 22 "unaware" in 5 and 4 focus groups, respectively) and 53 men (19 "aware" and 34 "unaware" in 3 and 4 focus groups, respectively) were included. A thematic analysis of transcripts was performed to explore knowledge and representations about OP, risk factors, prevention, and treatment. RESULTS: The data showed that both sexes, but especially men, had limited knowledge of OP and considered it as a natural aging process not related to fragility fractures. They generally did not feel concerned by OP and no important difference was observed between "aware" and "unaware" patients. Women expressed their fear of the disease, associated with aging and the end of life, while men considered it to be a women's disease only. Both sexes were aware of OP risk factors, but were suspicious towards treatments because of the associated side effects. CONCLUSION: Understanding people's representation of OP might help to provide patients with relevant information in order to optimize their preventive behavior and decrease the burden of the disease.

Secukinumab shows high efficacy irrespective of HLA-Cw6 status in patients with moderate-to-severe plaque-type psoriasis: SUPREME study.

BACKGROUND: Understanding genetic variations is important in predicting treatment response and forms the basis for identifying new pharmacogenetic and pharmacogenomic targets for psoriasis treatment. There are limited data on the efficacy of secukinumab in relation to genetic markers. OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg in HLA-Cw6-positive (Cw6-POS) and HLA-Cw6-negative (Cw6-NEG) patients with moderate-to-severe chronic plaque-type psoriasis. METHODS: SUPREME was a 24-week, phase IIIb study with an extension period up to 72 weeks. Primary end point was Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks. RESULTS: In total, 434 patients were recruited: 185 (42·6%) were Cw6-POS and 246 (56·7%) were Cw6-NEG (three not assessed). Mean ± SD age was 45·2 ± 13·2 years (Cw6-POS 42·7 ± 13·1; Cw6-NEG 47·2 ± 12·9). The baseline PASI score was comparable between the cohorts [Cw6-POS 20·7 ± 8·99; Cw6-NEG 21·5 ± 9·99 (P = 0·777)]. At week 16, PASI 90 was achieved in 80·4% of Cw6-POS and 79·7% of Cw6-NEG patients (difference 0·76; 95% confidence interval -7·04 to 8·23). No differences in absolute PASI at week 16 (Cw6-POS 1·36 ± 3·58; Cw6-NEG 1·18 ± 2·29) were observed. The overall safety profile of secukinumab was consistent with that previously reported. No statistically significant difference was detected in the rate of treatment-emergent adverse events [Cw6-POS 42·7%; Cw6-NEG 49·6% (P = 0·295)]. A high PASI 90 response was achieved with secukinumab with a fast reduction in absolute PASI. CONCLUSIONS: Determination of HLA-Cw6 status for secukinumab therapy is unnecessary, as it is highly effective regardless of HLA-Cw6 status.

A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior.

DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.

Consensus on the use of cyclosporine in dermatological practice. Italian Consensus Conference.

Cyclosporine A (CsA) efficacy and safety have been proven in various dermatoses both in adults and in children even as long-term treatment. Over the last 25 years, Italian dermatologists have gathered relevant experience about CsA treatment for psoriasis and atopic dermatitis. This paper has been developed by an Italian Consensus Conference and it is aimed at providing recommendations based on real-world clinical experience in adult patients, consistent with efficacy and safety data arising from the scientific literature. The paper is mainly focused on the analysis of the optimal therapeutic schemes for psoriasis and atopic dermatitis, in terms of doses and treatment duration, according to individual characteristics and to the severity of the disease. Moreover, it overviews ideal management, taking into account pharmacological interactions, influence of comorbidities, and the most common adverse events related to CsA treatment.

Methods for the assessment of the efficacy of products and slimming treatments for cellulite according to the Italian Interdisciplinary Group for the standardization of efficacy tests on cosmetic products.

Cellulite is a very common skin alteration with a complex pathogenesis; different degrees of severity of cellulite can be observed in most part of people after puberty, and numerous cosmetic or more invasive treatments have been proposed, with variable efficacy. Since reproducible methods of evaluation of the effectiveness of cellulite treatments are lacking, the purpose of our group was to define and set general testing principles for evaluating the efficacy of slimming products and treatments/remodeling methods for cellulite, to achieve a delineation of reliable and reproducible research steps following a well-designed and scientifically valid methodology. After a careful review of literature and textbooks and according to personal experience, we defined assessment protocols based on clinical and instrumental tools. In order to make studies reliable, reproducible and safe, a protocol standardization is needed. The sponsor is responsible for assuring quality and information concerning the product under investigation; moreover, investigators should be experienced on cellulite evaluation and treatment, and, finally, the duration and modalities of application of the product should be specified. A treated VS non treated area comparison can be performed, to evaluate the severity of cellulite and the clinical outcomes of the treatment. Besides clinical evaluation, instrumental methods should always be implemented to provide objective data for treatment outcome.

Cyclin D1, B and A expression and cell turnover in psoriatic skin lesions before and after cyclosporin treatment.

BACKGROUND: Cyclosporin induces a dramatic reversal to normality in psoriatic lesions, with a reduction of inflammatory infiltrate and epidermal proliferation. It is known that the cell cycle and cell proliferation are regulated by the sequential activation of cyclin-dependent kinase/cyclin complexes. AIM: We evaluated epidermal cell turnover and thickness, as well as the expression of cyclins D1, B and A in psoriatic skin before and after therapy with cyclosporin. METHODS: Epidermal thickness, mitotic and apoptotic indices (MI, AI), as well as the percentages of epidermal cell nuclei positive for Ki-67 and cyclins D1, B and A were calculated. Cytoplasmic positivity to cyclin B was also evaluated. RESULTS: After 6 weeks of therapy, we observed a clinical improvement of the disease and normalization of the epidermis. Epidermal thickness and Ki-67-, cyclins B- and A-positive nuclei percentage were significantly higher before therapy than after (0.52 +/- 0.05 mm vs. 0.21 +/- 0.03 mm, P < 0.001; 19 vs. 2.6, 19 vs. 3, and 12 vs. 1, respectively; P < 0.0005); cytoplasmic positivity to cyclin B was slightly higher before therapy (score 3 vs. 2-3). Cyclin D1 was negative or expressed in a low percentage of nuclei in psoriasis before therapy (0.78), whereas it was always negative after therapy. MI was 0.15 before therapy, whereas mitoses were almost absent afterwards. Apoptoses were undetectable before therapy, whereas a few apoptoses were observed after treatment (AI = 0.4). CONCLUSIONS: Overexpression of cyclins B and A, rather than D1 seems to characterize psoriasis. Their evaluation could provide further insights in understanding the development of this disorder and could be used to verify the efficacy of currently used therapies as well as future ones.

Sun and skin. Role of phototype and skin colour.

The study of the biological effects of sun on the skin is one of the most topical questions in the recent dermatological literature. Interest in these effects has grown since it was demonstrated that the sun accelerates intrinsic skin ageing and is a principal factor for skin cancer. Skin damage caused by the sun is mainly due to UV radiation. Skin damage certainly has ancient roots, but has undergone sudden changes since man began to migrate to different geographical areas, for example when northern European populations colonised sunny areas close to equator. It is not a coincidence that the highest incidence of sun induced neoplasias is observed among white population of Australia. This epidemiological finding focused the interest towards the identification of phenotypic factors conditioning skin response to sunlight, and hence towards the definition of the so called phototype. After the fundamental work of Fitzpatrick based on sun exposure history more recent studies have shown that skin response to UV-rays can be predicted, to a good approximation, by skin colorimetry. Therefore this simple, cheap and non invasive measurement enables to predict sun reactivity skin type and to evaluate the melanoma risk.

Quantitative characterization and study of the relationship between constitutive-facultative skin color and phototype in Caucasians.

In this study constitutive and facultative colorimetric values were quantified to determine the physiologic changes in Caucasian skin color and to define the correlation between skin color and phototype assessed according to the Fitzpatrick method. Our population consisted of 401 subjects ranging in age from 24 to 28 years with similar life styles. Skin color was measured with a Minolta CR-200 colorimeter on the upper medial quarter of the buttock (constitutive color) and on the cheek (facultative color). Advanced multivariate statistical analysis allowed differentiation between constitutive and facultative skin color in relation to the phototype to be quantified. Moreover, Kullback divergence showed that the probability of correctly determining a subject's phototype is high when the variables of constitutive and facultative skin color are considered together. This interesting result makes it possible, in the future, to use colorimetric values of exposed and nonexposed skin, together with determination of Fitzpatrick phototype and of other phenotypic characters, to better predict cutaneous sun reactivity.

Instrumental measurement of skin colour and skin type as risk factors for melanoma: a statistical classification procedure.

A statistical procedure to evaluate melanoma risk in Caucasian subjects on the basis of colorimetric measurement of skin colour and Fitzpatrick phototype is described. One hundred and sixty melanoma patients and 546 randomized healthy subjects of similar age, sex and place of origin were examined in the same period for skin colour using a tristimulus colorimeter and for Fitzpatrick phototype. A clinical score for classification purposes was obtained by statistical discriminant analysis with multivariate data transformation and dimension reduction techniques. A Fisher linear classifier was chosen for its simplicity and robustness in correctly predicting melanoma risk in new subjects. The classification rule was designed to avoid classifying subjects at high risk for melanoma as low risk, i.e. to give a negligible number of false negatives at the expense of more false positives. The procedure is objective and readily adapted to different clinical requirements. This is only a preliminary study but it is hoped that by performing more complex statistical analyses, e.g. neural networks, and adding other parameters (proven risk factors such as number of naevi) the performance will be further improved.

Altered expression of the alpha2 laminin chain in psoriatic skin: the effect of treatment with cyclosporin.

The histopathological pattern of psoriasis is characterized by dermal inflammatory reaction and hyperproliferation of the epidermis. The mechanism of the epidermal hyperproliferation is not completely understood, but it is probably modulated by the basal lamina (BL), the alterations of which have not been described. We performed the present study to evaluate the expression of the alpha1, alpha2, beta1 and gamma1 laminin chains and collagen IV in the BL of active psoriasis vulgaris before and after cyclosporin treatment administered until the psoriasis was in remission. The results showed that the alpha2 chain is weak and irregular in the lesions, while the alpha1, beta1 and gamma1 chains and collagen IV are normal, with intense and continuous reaction. In the same subjects, this alteration was absent in skin that was clinically unaffected. After treatment with cyclosporin, the altered expression of the alpha2 chain returned to normal in the healing lesions.

Relationship between minimal phototoxic dose and skin colour plus sun exposure history: a neural network approach.

Before beginning PUVA-therapy it is important to accurately gauge an individual's degree of psoralen photosensitivity. This determination is usually based on an individual's skin phototype or minimal phototoxic dose. Since minimal phototoxic dose is technically complex and time consuming to measure, sun reactivity skin phototype is often used instead; however, it has recently been shown that skin phototype lacks specificity as a predictor of an individual's minimal phototoxic dose. In this study, an artificial neural network was developed to attempt to predict the minimal phototoxic dose from skin colour measurements combined with skin phototype. Our results showed that minimal phototoxic dose was predicted with an error less than 1 J/cm2 in only about half the subjects. In conclusion, minimal phototoxic dose probably cannot be predicted with sufficient accuracy on the basis of skin colour and skin phototype alone.

Relationship between skin color and sun exposure history: a statistical classification approach.

In this study our aim was to determine the biophysical values of constitutive skin color in Caucasians and to define the correlation between skin color and phototype assessed according to the Fitzpatrick method. Constitutive skin color was measured on the buttock, with a Minolta CR-200 colorimeter, in a population-of 557 consecutive subjects belonging to phototype categories I, II, III and IV. The colorimeter expresses the results in five different color systems. We used the "Yxy" and L*a*b* systems, which are the most widespread in dermatology. Statistical analysis of the data showed that the "Yxy" system is even more discriminant than the L*a*b* system when the Fitzpatrick classification scheme is adopted as the reference and shows a poor ability to correctly classify the intermediate phototypes (II and III). On the contrary the "Yxy" system performs well in distinguishing phototypes I and IV. To establish whether this low discriminating capacity for phototypes II and III is related to a low discriminating capacity of the method suggested by Fitzpatrick or by our procedure, an objective technique (minimal erythemal dose) should be used to evaluate the percentage errors of classification of both the Fitzpatrick method and instrumental measurement of skin color. The results of such a study are extremely important because the evaluation of skin color is objective, simple and has potential applications in dermatology and cosmetology.